Researchers at the University of Pittsburgh have discovered a biomarker that can predict which cognitively healthy individuals will develop Alzheimer’s disease (AD), and helps unravel the mystery of why some people whose brains show high levels of amyloid aggregates never go on to develop the neurological disorder. The investigators, whose findings appear in the journal Nature Medicine, demonstrate that star-shaped brain cells called astrocytes are key in driving progression of AD.
The research tested the blood of more than 1,000 cognitively-unimpaired people with and without amyloid pathology and found that those with amyloid burden and blood biomarkers that indicated abnormal astrocyte activation would progress to symptomatic AD in the future. The finding could be key to the development of future treatments to halt progression of the disease.
“Our study argues that testing for the presence of brain amyloid along with blood biomarkers of astrocyte reactivity is the optimal screening to identify patients who are most at risk for progressing to Alzheimer’s disease,” said senior author Tharick Pascoal, MD, PhD, associate professor of psychiatry and neurology at Pitt. “This puts astrocytes at the center as key regulators of disease progression, challenging the notion that amyloid is enough to trigger Alzheimer’s disease.”
The key indicator of Alzheimer’s disease is the aggregation of amyloid plaques, clumps of proteins that collect between nerve cells in the brain, as well as tau tangles that form inside neurons. Volumes of research has pointed to the accumulation of amyloid plaques and tau tangles as the main culprits in the development of AD. As a result, drug development efforts have focused on developing treatments targeting amyloid and tau, but haven’t delved into addressing other brain processes that may drive AD progression.
But recent advances by Pascoal’s lab have pointed to the disruption of other brain processes, such as inflammation that may be as important as amyloid burden in triggering the cascade of neuronal death that results in cognitive impairment. Now, building on these earlier findings, the team has found a biomarker that can predict the development of impairment via a simple blood test.
Astrocytes, which support neuronal cells by supplying them with oxygen and nutrients help protect these cells from pathogens. But because they don’t play a direct role in the how neurons communicate with one another, they have not been the focus of investigation.
“Astrocytes coordinate brain amyloid and tau relationship like a conductor directing the orchestra,” said Bruna Bellaver, Ph.D., postdoctoral associate at Pitt and lead author of the study. “This can be a game-changer to the field, since glial biomarkers in general are not considered in any main disease model.”
In this new study, the Pitt investigators tested blood samples in three independent studies of cognitively unimpaired elderly people for biomarkers of astrocyte reactivity—glial fibrillary acidic protein, or GFAP—along with the presence of pathological tau. The study showed that only those who were positive for both amyloid and astrocyte reactivity showed evidence of progressively developing tau pathology, indicating predisposition Alzheimer’s disease symptoms.
The researchers note that amyloid-positive individuals do not always progress to clinical AD symptoms, so it is not a strong enough biomarker to suggest treatment. The inclusion of a new biomarker predicting Alzheimer’s, such as GFAP, will allow for both improved identification of patients likely to progress to clinical symptoms, as well as indicate future directions for drug development and clinical trials.
